Tumor Suppressor Gene — Cellular Genetic Brakes

Tumour suppressor genes encode proteins responsible for cell cycle checkpoints, DNA repair mechanisms, and apoptosis. Under normal conditions, they maintain genomic stability by pausing cell proliferation to allow for nucleotide excision or mismatch repair. Well-known tumour suppressors include TP53, BRCA1, BRCA2, PTEN, and RB1.

In accordance with the classical 'two-hit hypothesis', both alleles of a tumour suppressor gene typically must be inactivated through mutation, deletion, or epigenetic silencing to promote cancer. Unlike oncogenes—which become hyperactive through single gain-of-function mutations—tumour suppressors foster malignancy through a loss-of-function mechanism, leaving cells vulnerable to uncontrolled division.

Identifying mutations in tumour suppressor genes informs both hereditary cancer risk assessments and specific treatment selections. Carrying an inherited mutation in genes like BRCA1 or BRCA2 substantially increases lifetime cancer risks, prompting specialised surveillance or risk-reducing interventions. Furthermore, identifying these alterations directs the use of targeted therapies designed to exploit the tumour's lost repair pathways.

Tumour suppressor status is evaluated through genomic sequencing of blood or saliva (for inherited germline mutations) or tumour tissue (for acquired somatic alterations). Next-generation sequencing panels, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA) detect point mutations, frameshifts, and large chromosomal deletions.

Inactivation of tumour suppressor genes occurs across nearly all cancers. TP53 is mutated in more than half of all human malignancies. BRCA1 and BRCA2 loss characterizes hereditary breast, ovarian, prostate, and pancreatic cancers. RB1 loss is central to retinoblastoma and small cell lung cancer, while PTEN alterations are common in endometrial, prostate, and glioblastoma tumours.

Because restoring lost gene function directly is challenging, modern therapies exploit the vulnerabilities created by their absence, a concept known as synthetic lethality. For instance, tumours with inactive BRCA1 or BRCA2 suppressor genes rely entirely on alternate DNA repair pathways, rendering them exceptionally sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors.